The primary goal of this P01 is to improve the outcomes and lives of patients with thyroid cancer by identifying genetically "at-risk" individuals allowing for early diagnosis and prediction of tumor behavior, new pathways that influence cancer development and progression, and improving outcomes of patients with metastatic disease by improving existing therapies or validating new treatment targets. Several factors support the importance of applying these efforts to thyroid cancer: (1) Thyroid cancer incidence is rising at the fastest rate of all malignancies in the United States. (2) Thyroid cancer typicall takes an indolent course when patients are diagnosed early, thus with the increasing incidence there is an ever enlarging population of individuals surviving long-term. (3) For patients with more aggressive forms of thyroid cancer, current treatment options need to be improved or replaced with more effective treatments. Over the course of the first cycle of this P01 our group has together worked toward these goals and made key observations with potential to impact on patients with differentiated thyroid cancer (papillary and follicular). The goal for this competing renewal is to extend the work on the most promising findings that have greatest likelihood to be translated into practice or that represent key advances in the field with potential to alter paradigms used in research or clinical practice. Specifically, we will functionally characterize genes that predispose to PTC in families identified in the first cycle of the P01 and apply new technologies to a larger number of informative families to identify more potential genes that predispose to PTC (Project 1), extend the work using a candidate gene approach for FTC and PTC risk that has identified interactions between signaling pathways (Project 2);design approaches to enhance 1-131 therapy using novel mouse imaging techniques developed in the P01 and extend that work to identify other unknown regulators of this process (Project 3);and fully determine the role and potential therapeutic importance of p21 activated kinase (PAK), a newly identified signaling pathway downstream of BRAF, in thyroid cancer in vivo, and determine its role in resistance to RAF inhibitors (Project 4).
Thyroid cancer incidence is rising. Key issues in clinical care relate to defining the risk of developing thyroid cancer, identifying key pathways involve in tumor formation or predisposition, developing methods to improve existing treatments, and defining pathways involved in disease progression to develop new therapies. This P01 addresses these critical areas to improve the outcomes of patients with thyroid cancer.
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|Wójcicka, Anna; Czetwerty?ska, Ma?gorzata; ?wierniak, Micha? et al. (2014) Variants in the ATM-CHEK2-BRCA1 axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma. Genes Chromosomes Cancer 53:516-23|
|Pringle, Daphne R; Vasko, Vasily V; Yu, Lianbo et al. (2014) Follicular thyroid cancers demonstrate dual activation of PKA and mTOR as modeled by thyroid-specific deletion of Prkar1a and Pten in mice. J Clin Endocrinol Metab 99:E804-12|
|McCarty, Samantha K; Saji, Motoyasu; Zhang, Xiaoli et al. (2014) BRAF activates and physically interacts with PAK to regulate cell motility. Endocr Relat Cancer 21:865-77|
|Lakshmanan, Aparna; Scarberry, Daniel; Shen, Daniel H et al. (2014) Modulation of sodium iodide symporter in thyroid cancer. Horm Cancer 5:363-73|
|Wojcicka, A; de la Chapelle, A; Jazdzewski, K (2014) MicroRNA-related sequence variations in human cancers. Hum Genet 133:463-9|
|Stechschulte, Lance A; Wuescher, Leah; Marino, Joseph S et al. (2014) Glucocorticoid receptor ? stimulates Akt1 growth pathway by attenuation of PTEN. J Biol Chem 289:17885-94|
|Ngeow, Joanne; Stanuch, Kim; Mester, Jessica L et al. (2014) Second malignant neoplasms in patients with Cowden syndrome with underlying germline PTEN mutations. J Clin Oncol 32:1818-24|
|Medici, Marco; Porcu, Eleonora; Pistis, Giorgio et al. (2014) Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease. PLoS Genet 10:e1004123|
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